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Trial record 30 of 33 for:    "Ewing Sarcoma" | "Vincristine"

A Phase I Dose Finding Study in Children With Solid Tumors Recurrent or Refractory to Standard Therapy

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ClinicalTrials.gov Identifier: NCT02085148
Recruitment Status : Active, not recruiting
First Posted : March 12, 2014
Last Update Posted : November 15, 2019
Sponsor:
Information provided by (Responsible Party):
Bayer

Brief Summary:

Dose escalation phase of the study :

To define the safety profile, maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of regorafenib administered orally as a single agent in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days in pediatric subjects with solid malignant tumors recurrent or refractory to standard therapy. To characterize the pharmacokinetics (PK) of regorafenib The dose escalation phase of the study has been completed.

Expansion phase:

To define the safety profile, MTD and the RP2D of regorafenib administered orally in combination with backbone chemotherapy (vincristine and irinotecan) at relapse in pediatric subjects with rhabdomyosarcoma (RMS) and other solid malignant tumors recurrent or refractory to standard therapy.


Condition or disease Intervention/treatment Phase
Pediatric Oncology Drug: Regorafenib (BAY73-4506) Drug: Vincristine (Cellcristin®) Drug: Irinotecan (Irinotecan Cell pharm®) Phase 1

Detailed Description:

Expansion Phase of the study:

Subjects must have relapsed/refractory RMS or a solid malignant tumor (Ewing sarcoma, hepatoblastoma, neuroblastoma and Wilms tumor).


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 62 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Multi-center, Open-label, Non-randomized, Phase I Dose Escalation Study of Regorafenib (BAY 73-4506) in Pediatric Subjects With Solid Malignant Tumors That Are Recurrent or Refractory to Standard Therapy.
Actual Study Start Date : April 11, 2014
Actual Primary Completion Date : May 5, 2019
Estimated Study Completion Date : April 11, 2022


Arm Intervention/treatment
Experimental: Sequential dosing schedule
Expansion phase: Schedule B - Sequential dosing schedule: Of a 21-day cycle, regorafenib will be dosed sequentially, following administration of VI: Vincristine:intravenous bolus, 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg), Day 1 and Day 8. Irinotecan: intravenously over 1 hour, 50mg/m2/day, Day 1 to Day 5. Regorafenib: orally, at a starting dose level of 72 mg/m2 (subjects 2 to less than 18 years old) or 60 mg/m2 (subjects 6 to less than 24 months old) once daily, Day 8 to Day 21.
Drug: Regorafenib (BAY73-4506)
Regorafenib will be given orally once a day, across cycles of 21 days each. During each cycle regorafenib is taken for 2 weeks followed by one week off the drug. Doses of the study drug used in this study are age-dependent and the children's dose will been adjusted based on the age and the body surface area and given either as tablets or granulate.

Drug: Vincristine (Cellcristin®)
Vincristine will be given at a dose of 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg, maximum 2.0 mg) on Day 1 and Day 8 in 21-day cycles.

Drug: Irinotecan (Irinotecan Cell pharm®)
Irinotecan will be administered at a starting dose of 50 mg/m2/day from Day 1 to Day 5, in 21 day cycles.

Experimental: Concomitant dosing schedule
Expansion phase: Schedule A - Concomitant dosing schedule: Of a 21-day cycle, regorafenib will be concomitantly administered with vincristine and irinotecan (VI): Vincristine: intravenous bolus, 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg), Day 1 and Day 8. Irinotecan: intravenously over 1 hour, 50 mg/m2/day, Day 1 to Day 5. Regorafenib: orally, at a starting dose level of 72 mg/m2 (subjects 2 to less than 18 years old) or 60 mg/m2 (subjects 6 to less than 24 months old) once daily, Day 1 to Day 14.
Drug: Regorafenib (BAY73-4506)
Regorafenib will be given orally once a day, across cycles of 21 days each. During each cycle regorafenib is taken for 2 weeks followed by one week off the drug. Doses of the study drug used in this study are age-dependent and the children's dose will been adjusted based on the age and the body surface area and given either as tablets or granulate.

Drug: Vincristine (Cellcristin®)
Vincristine will be given at a dose of 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg, maximum 2.0 mg) on Day 1 and Day 8 in 21-day cycles.

Drug: Irinotecan (Irinotecan Cell pharm®)
Irinotecan will be administered at a starting dose of 50 mg/m2/day from Day 1 to Day 5, in 21 day cycles.

Experimental: Dose escalation
Dose escalation phase: This phase of the study has been completed
Drug: Regorafenib (BAY73-4506)
Regorafenib will be given orally once a day, across cycles of 21 days each. During each cycle regorafenib is taken for 2 weeks followed by one week off the drug. Doses of the study drug used in this study are age-dependent and the children's dose will been adjusted based on the age and the body surface area and given either as tablets or granulate.




Primary Outcome Measures :
  1. Safety: Maximum Tolerated Dose [ Time Frame: approximately after 21 months ]
    MTD is defined as the dose level at which none or 1 of 6 participants experiences dose-limiting toxicity (DLT), when at least 2 of 3-6 participants experience a DLT at the next highest dose

  2. Safety: Recommended Phase II Dose [ Time Frame: approximately after 21 months ]
    In order to establish a RP2D, the MTD cohort will be expanded to have at least 12 evaluable subjects to confirm the RP2D. It is expected that at least 15 subjects evaluable for DLTs will be necessary to establish the RP2D of the combination"

  3. Number of participants with Adverse Events [ Time Frame: Dose escalation phase:approximately after 21 months; Expansion Phase: approximately after 21 months ]
    Individual listings of adverse events will be provided. The incidence of treatment-emergent adverse events and drug-related adverse events, respectively, will be summarized by worst NCI-CTCAE v 4.0 grade and by dose level

  4. AUC(0-24)md based on nominal dosing [ Time Frame: Dose escalation phase:Cycle 1 Day 1, Day 15 and Day 21 ]
    Dose escalation phase has been completed


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months ]
  2. Time to progression [ Time Frame: Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months ]
  3. Tumor response: tumor assessment by RECIST v. 1.1 [ Time Frame: Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months ]
  4. Taste and texture questionnaire of the regorafenib formulations [ Time Frame: Dose escalation phase: Cycle 1; Expansion phase:Concomitant: Cycle 1 Day 1;Sequential: Cycle 1 Day 8 ]
    Expansion phase Dose escalation phase

  5. AUC(0-24)md based on nominal dosing [ Time Frame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21 ]
    Expansion phase

  6. Cmax(0-24)md based on individual dosing [ Time Frame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21 ]
    Expansion phase

  7. Cav(0-24)md based on individual dosing [ Time Frame: Expansion phase:Cycle 1 Day1, Day 15 and Day 21; Dose escalation phase:Cycle 1 Day1, Day 15 and Day 21 ]
    Expansion phase Dose escalation phase

  8. t1/2eff,md based on individual dosing [ Time Frame: Expansion phase:Cycle 1 Day1, Day 15 and Day 21; Dose escalation phase:Cycle 1 Day1, Day 15 and Day 21 ]
    Expansion phase Dose escalation phase

  9. AUC(0-24)md based on individual dosing [ Time Frame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21 ]
    Expansion phase

  10. Clearance of irinotecan and SN-38 [ Time Frame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21 ]
    Expansion phase



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed Informed Consent Form by subjects and/or subjects' parents/legal guardians and age appropriate Assent Form by the subjects obtained before any study specific procedure
  • Age: from 6 months to less than 18 years old
  • Diagnosis, Dose escalation phase of the study: subjects must have had histologic verification of solid malignancy at original diagnosis. Subjects with recurrent or refractory solid tumors are eligible, including primary central nervous system (CNS) tumors or subjects with known CNS metastases. Subject's current disease state must be one for which there is no known effective therapy or therapy proven to prolong survival with an acceptable quality of life. Effective therapy may include surgery, radiation therapy, chemotherapy or any combination of these modalities.

Dose expansion phase of the study: subjects must have relapsed/refractory RMS or a solid malignant tumor (Ewing sarcoma, hepatoblastoma, neuroblastoma and Wilms tumor) in which treatment with vincristine/irinotecan is considered backbone chemotherapy at relapse and a scientific rationale to combine vincristine/irinotecan with regorafenib exists.

  • Subjects must have at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. For the neuroblastoma subjects with osteomedullary disease, the SIOPEN (International Society of Pediatric Oncology Europe Neuroblastoma Group) score will be used. Bone scans (if clinically indicated) should be obtained ≤12 weeks prior to the start of treatment.
  • Life expectancy of at least 12 weeks from the time of signing informed consent/assent.
  • Performance level: Karnofsky ≥ 70% for subjects > 12 years of age or Lansky ≥ 70% for subjects ≤ 12 years of age
  • Adequate hematological function assessed by the following laboratory requirements conducted within 7 days before starting study treatment:

Peripheral absolute neutrophil count (ANC): ≥ 1.0 x 10*9/L Platelet count : ≥ 100 x 10*9/L (transfusion independent) Hemoglobin: ≥ 8.0 g/dL

-Adequate hepatic function defined as:

  • Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤ 3.0* ULN
  • Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 * ULN

Exclusion Criteria:

  • Prior treatment with regorafenib. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study.
  • Dose expansion phase of the study only: Subjects with brain tumors or subjects with known CNS metastases are excluded.
  • Subjects with uncontrolled baseline hypertension higher than Grade 1 NCICTCAE v. 4.0
  • Subjects with evidence or history of disorders of coagulation or thrombosis
  • Cardiac abnormalities and cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
  • History of organ allograft (including allogeneic bone marrow transplant)
  • Any other malignant disease treated prior to study entry
  • Pregnancy or breast feeding
  • Significant gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease or any malabsorption condition
  • Close affiliation with the investigational site, e.g. a close relative of the investigator or a dependent person (e.g. employee or student of the investigational site)
  • Unresolved toxicity higher than NCI-CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure (excluding alopecia, chemotherapy-induced ototoxicity, Grade 2 chemotherapy-induced neuropathy and, as per above eligibility criteria, anemia with hemoglobin ≥ 8 mg/dL and ANC ≥ 1.0 x 10 9/L ).
  • Any other malignant disease treated prior to the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02085148


Locations
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France
Lyon Cedex, France, 69008
Marseille, France, 13005
Paris, France, 75005
Villejuif Cedex, France, 94805
Italy
Genova, Liguria, Italy, 16147
Milano, Lombardia, Italy, 20133
Spain
Madrid, Spain, 28009
Valencia, Spain, 46026
United Kingdom
Sutton, Surrey, United Kingdom, SM2 5PT
Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE1 4LP
Birmingham, West Midlands, United Kingdom, B4 6NH
Manchester, United Kingdom, M13 9WL
Sponsors and Collaborators
Bayer
Investigators
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Study Director: Bayer Study Director Bayer

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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02085148     History of Changes
Other Study ID Numbers: 15906
2013-003579-36 ( EudraCT Number )
First Posted: March 12, 2014    Key Record Dates
Last Update Posted: November 15, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Pediatric cancer
Rhabdomyosarcoma,
Ewing sarcoma
Hepatoblastoma
Neuroblastoma
Wilm's tumor
Additional relevant MeSH terms:
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Vincristine
Neoplasms
Irinotecan
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators